INFLUENCE OF METABOLIC DISORDERS ON CHRONIC DISEASE BURDEN AND HEALTH OUTCOMES

Chronic diseases represent an escalating global health burden, with metabolic dysfunction and systemic inflammation emerging as central and interconnected biological drivers across multiple organ systems. This thesis investigates the relationship between metabolic-inflammatory dysregulation and chronic disease through three complementary studies addressing treatment response, diagnostic precision, and disease outcomes in severe asthma, neurocognitive decline, and non-alcoholic fatty liver disease respectively. Study 1 examined whether obesity modulates the long-term effectiveness of biologic therapy in severe asthma in a real-world cohort of nearly 2,100 patients from the SANI registry. Despite presenting with a clinically more complex profile obese patients achieved sustained and comparable improvements across all key outcomes, including exacerbation frequency, asthma control, lung function, and clinical remission, over up to four years of follow-up. These findings provide strong evidence that biologic therapy remains equally effective regardless of BMI. Study 2 investigated whether a multidimensional biological-cognitive approach could improve diagnostic discrimination along the neurocognitive continuum in approximately 100 geriatric outpatients spanning five diagnostic categories from Subjective Cognitive Complaint to Major Neurocognitive Disorder. A progressive Firth-penalized logistic regression model sequentially integrating neuropsychological performance, body composition, metabolic markers, and inflammatory cytokine profiling produced consistent discriminative gains across five clinically relevant pairwise comparisons. The inflammatory cytokine component provided the largest biological increment for the most diagnostically challenging early-stage comparisons, suggesting that peripheral inflammatory dysregulation may represent a biological signature of the earliest neurocognitive transitions. Multidimensional scaling and hierarchical cluster analysis identified a biologically structured two-dimensional profile space and two discrete biological phenotypes mapping coherently onto clinical diagnosis, supporting a shift toward comprehensive biological-cognitive patient characterisation in geriatric cognitive medicine. Study 3 investigated the impact of pandemic-related lifestyle changes on clinical outcomes in a prospectively monitored NAFLD cohort. Lockdown-imposed reductions in physical activity and increases in caloric intake were associated with worsening anthropometric, biochemical, and body composition parameters alongside accelerated liver disease progression and a marked increase in hepatocellular carcinoma occurrence. Body compartment alterations emerged as the main independent predictor of HCC risk, beyond established factors including liver stiffness, identifying body composition as a dynamic prognostic modifier in NAFLD. Collectively, these studies provide convergent evidence that metabolic status is not a passive comorbidity but an active biological determinant of disease expression, diagnostic classification, and clinical outcomes.